Organophosphorus insecticides, which are currently the most important class of insecticides, are biochemically reactive chemicals and form various types of covalent bonds with vital macromolecules of the cell. Therefore, these compounds can attack a multiplicity of macromolecular targets besides the well-established primary target, acetylcholinesterase of neural synapses. Interaction with some of these secondary targets leads to overt side effects such as delayed neurotoxicity and teratogenicity. Many others, however, result in more subtle alterations of biochemical balance which may have discrete consequences under specific conditions. Two such interactions, the release of liver B-glucuronidase and inhibition of mixed-function oxidases, have been selected for this study. Both involve covalent bonding with a reactive electrophile for which the rat liver is simultaneously the target and the modifier. Structural heterogeneity within the liver is a critical factor in both respects and will be emphasized. This project seeks to clarify the biochemical mechanisms involved in these side effects and the influence of the metabolic activities of the liver on these side effects. Techniques employed will include in vivo analyses, in situ liver perfusions and the use of isolated hepatocytes and intralobular subpopulations of hepatocytes. 35S and 14C-labeled organophosphates including parathion, SV1, fenitrothion and diazinon will be used to trace the covalent bond formation as well as their metabolic fates. Besides rats, mice and chickens may also be used.